S-acylimino-x



5-ACYLIM1NO-4-MONONUCLEAR-ARYL-SUBSTI- TUTED-A -1,3,4 THIADIAZOLINE-2-SULFIDES AND METHOD OF PREPARING THE SAME Richard W. Young, Riverside, Kathryn H. Wood, Greenm'ch, and Melinda J. Muller, Stamford, Conn., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application January 23, 1956,

Serial No. 560,865

11v Claims. (Cl. 260306.8)

This inventionrelates to new organic compounds and more particularly is concerned with the preparation of novel 5 acylimino 4 mononuclear aryl substituted- A -l,3,4 thiadiazoline 2 sulfides of the formula:

wherein R1 is a hydrogen atom, a lower alkyl radical or a monocyclic aralkyl radical, and R2 is a monocyclic aryl radical. Suitable lower alkyl substituents are methyl, ethyl, propyl, isopropyl, butyl, pentyl, amyl, hexyl, etc.; suitable aralkyl substituents are benzyl, phenethyl, phenylpropyl, phenylbutyl, etc.; and suitable aryl substituents are exemplified by phenyl and substituted phenyl, suitable substituents on the phenyl ring being -Cl, Br,' I, Nz, and lower alkyl radicals containing from 1 to 4 carbon atoms.

The compounds of the present invention find utility as intermediates for the preparation of novel 5 acylimino-4- mononuclear-aryl substituted A 1,3,4 thiadiazoline- 2-sulfonamides which are more particularly described and claimed in the copending application of Richard W. Young and Melinda J. Muller, Serial No. 560,866, filed concurrently herewith. The compounds of :the aforesaid copending application are efiective natriuretic agents, that is agents which enhance the excretion of sodium in the urine without necessarily changing the normal volume of urine excreted.

As described more in detail in the aforesaid application, the novel thiadiazolinc sulfides of this invention can be smoothly converted and in good yield to the corresponding sulfonylchloride derivatives which are then amidated by reaction with liquid ammonia to form the final compounds, namely, the 5 acylimino 4 mono nuclear aryl substituted A 1,3,4 thiadiazoline-Z- I sulfonamides.

The thiadiazoline sulfides of this invention are preferably prepared by reacting an acyl isothiocyanatc, such as acetylisothiocyanate, with a suitable 3 mononucleararyl substituted dithiocarbazate, such as 3 phenylbenzyldithiocarbazate, in the presence of a suitable nonhydroxylated organic solvent, such as toluene or dimethylformamide, by heating to reflux temperatures, that is temperatures of the order of 25 C. to 150 C., maintaining the heating until the evolution of hydrogen sulfide nearly ceases and thereafter removing the solvent by distillation. The thiadiazoline sulfide may then be recovered and purified by recrystallization in a standard manner.

A variety of 3 mononuclear aryl substituted-dithiocarbazates may be used in carrying out this invention such as, for example, 3 phenylbenzyldithiocarbazate, 3 m tolyl)benzyldithiocarbazate, 3 (p bromophenyl)- benzyldithiocarbazate, 3 (p-chlorophcnyl)benzyldithiocarbazate, 3 (p-iodophenyl)benzyldithiocarbazate, 3-(pacetamidophenyl) benzyldithiocarbazate, 3 (m-methoxyphenyl)benzyldithiocarbazate, 3 (3,4 dichlorophenyl)- The invention will be described in greater detail in conjunction with the following specific examples in which the parts are by weight unless otherwise specified.

EXAMPLE 1 S-acetylimino-4-phenyl-2-benzylmercapt0-A 1,3,4-thiadiazoline To a solution of parts by volume of toluene and 7.4 parts of acetylisothiocyanate (J. Chem. Soc., 89, 564) there was added 20 parts of 3-phenylbenzyldithiocarbazate (J. Prakt. Chem., [2], 60, 218). After several minutes of heating at reflux a complete solution was obtained, and heating was maintained for 6 hours. During this time hydrogen sulfide was evolved. At the end of the refluxing period, very little hydrogen sulfide was being evolved and the solution was dark red. The toluene was removed by vacuum distillation. The red solid that remained was dissolved in 165 parts by volume of hot methanol. After cooling, the solid obtained was filtered oil? and washed with ether yielding a golden solid which had a melting point of -98 C. This product was recrystallized-from '105 parts by volume of methanol- The yellow solid was washed with ether yielding a purified product having a melting point of 101102 C.

EXAMPLE 2 5-acetylimino-4-(m-tolyl) -2-benzylmercapt0- A -1,3,4-thiadiaz0line The same reaction conditions were used as in Example 1 employing 5 parts of 3-(m-tolyl)benzyldithiocarbazate,

1.7 parts of acetylisothiocyanate and 20 parts by volume of toluene. The reaction mixture was refluxed for only one hour. The product was recrystallized twice from 95% alcohol and washed with hexane to give a product having a melting point of 107-108 C.

EXAMPLE 3 S-acetylimino-l-(p-bromophenyl)-2-benzylmercapto- A l ,3,4-2hiadiazoline .86-88 C. The sample was recrystallized from methanol again and the purified product had a melting point of 91-92" C.

EXAMPLE 4 5 -acetylimino-4-( p-chlorophenyl)-2-benzylmercapto- A -I,3,4-thiadiazoline The same reaction conditions were used as in Example -Patented Feb. 26, 1957' 1 employing 6.5 parts of 3-(p-chlorophenyl)benzyldithio- I carbazate, 2.14 parts of acetylisothiocyanate and 25 parts by volume of toluene. The reaction mixture was refluxed for 3.5 hours. The product was recrystallized twice from 95% alcohol to give a product melting at 84-85 C- A sample was recrystallized from methanol. with charcoal treatment yielding a purified product having a melting point of 88-89 C.

The following compounds may be prepared by following the procedure described in Example 1, employing as the starting material the appropriate acyl isothiocyanatc and 3-substituted carbazate: 5-formylimino-4-pheny1-2- benzylmercapto-M-1,3,4-thiadiazoline, S-propionylimino- 4 (p-iodophenyl) 2 benzylrnercapto A 1,3,4-thiadiazoline, 5 butyrylimino-4-(p-acetamidophenyl)-2benzylmercapto A 1,3,4 thiadiazoline, 5-valyrylimino4-(mmethoxyphenyl) 2 benzylmercapto A 1,3,4 thiadiazoline, 5 phenacetylimino 4 (3,4 dichlorophenyl)- 2 benzylmercapto n 1,3,4 thiadiazoline, and 5 isobutyrylimino 4 (p-isopropylphcnyl) 2 benzylmercapto A 1,3,4 thiadiazoline.

We claim:

1. 5 acylimino 4 mononuclcar-aryl-substituted-A 1,3,4-thiadiazoline-Z-sulfides of the formula:

wherein R1 is selected from the group consisting of a 6. The method of preparing 5-acylirnino-4-mono nuclear-aryl-substituted-A 1,3,4-thiadiazoline-Z-sulfides of the formula:

wherein R1 is selected from the group consisting of a hydrogen atom, a lower alkyl radical and a phenyl-loweralkyl, and R2 is selected from the group consisting of phenyl, halo-substituted phenyl, lower alkyl-substituted phenyl, lower alkoxy-substituted phenyl, amido-substituted phenyl, and nitro-substituted phenyl radicals, which comprises reacting an acyl isothiocyanate with a 3-mononuclear-aryl-substituted-dithioearbazatc in the presence of a non-hydroxylated organic solvent under reflux conditions.

7. The method according to claim 6 in which the isothiocyanate is acetylisothiocyanate.

8. The method of preparing 5-acetylimino-4-phenyl-2- benzylmercapto-M-l,3,4-thiadiazoline which comprises reacting acetylisothiocyanate with 3-phenylbenzyldithiocarbazate in the presence of toluene under reflux conditions.

9. The method of preparing 5acetylin1ino-4-(m-tolyl)- Z-benZyImercaptO-A -1,3,4-thiadiazoline which comprises reacting acetylisothiocyanate with 3-(m-tolyl)benzyldithiocarbazate in the presence of toluene under reflux conditions.

10. The method of preparing 5-acetylimino-4-(pbromophenyl)-2-benzylmercapto A 1,3,4-thiadiazoline which comprises reacting acetylisothiocyanate with 3- (p-bromophenyl)benzyldithiocarbazate in the presence of toluene under reflux conditions.

11. The method of preparing 5 acctylimino 4 (pchlorophenyl)-2-benzylmercapto A 1,3,4-thiadiazoline which comprises reacting acetylisothiocyanate with 3-(p-chlorophenyl)benzyldithiocarbazate in the presence of toluene under reflux conditions.

No references cited. 

1. 5-CYLIMINO -4- MONONUCLEAR-ARYL-SUBSTITUTED-$2 1,3,4-THIADIAZOLINE-2-SULFIDES OF THE FORMULA: WHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF A HYDROGEN ATOM, A LOWER ALKYL RADICAL AND A PHENYL-LOWER ALKYL, AND R2 IS SELECTED FROM THE GROUP CONSISTING OF PHENYL, HALO-SUBSTITUTED PHENYL, LOWER ALKYL-SUBSTITUTED PHENYL, LOWER ALKOXY-SUBSTITUTED PHENYL, AMIDO-SUBSTITUTED PHENYL, AND NITRO-SUBSTITUTED PHENYL RADICALS. 